Menu
When liver slices were incubated with TNFα in the absence of albumin, researchers observed changes in mitochondria density, size and shape that were partially rescued in the presence of albumin. Interestingly, abnormal ultrastructural features in hepatocyte mitochondria appeared not to alter the mitochondrial membrane potential, an essential component in the process of energy production during oxidative phosphorylation. In the absence of albumin, TNFα induced mitochondrial oxidative stress. However, the increase of hepatocyte mitochondrial respiration was not associated with an increase in energy production and albumin appeared not to modulate any of these processes. Instead, albumin reduced TNFα-induced fatty acid β-oxidation – the process by which fatty acids are broken down to produce energy. The authors found that exposure to TNFα favored the use of acetyl-carnitine over isocitrate as energy substrate. Indeed, TNFα led to a breakpoint after isocitrate in the tricarboxylic acid cycle – the major energy-yielding metabolic pathway in the cell – that was counteracted by albumin. In contrast, when hepatocytes were submitted to transcriptional arrest, TNFα led to a different breakpoint in the tricarboxylic acid cycle that resulted in the accumulation of succinate. Under transcriptional arrest conditions, deregulation of the tricarboxylic acid cycle by TNFα was not only rescued by albumin, but albumin had also the ability to prioritize succinate as energy substrate.
The antioxidant action of albumin appeared to be mediated via activating transcription factor 3 (ATF3) – a key modulator of the response to oxidative stress. Indeed, hepatocytes cultured with TNFα in the presence of albumin, showed increased expression of the Atf3 gene and ATF3 protein. These observations were confirmed in vivo using a mouse model of TNFα-induced liver injury, providing further evidence of the mechanism by which albumin contributes to preserving hepatocyte mitochondria function and liver homeostasis.
“It is well characterized that albumin is an effector molecule that once internalized by cells is able to block endosomal Toll-like receptor signaling, lysosomal cathepsin B leakage, mitochondrial cytochrome c release and caspase-3 activity. In this study we have also discovered the antioxidant protective actions of albumin in hepatocytes through the activation of the common stress-responsive transcription factor ATF3”, said Marta Duran-Güell, leading author on the paper and post-doctoral researcher at Inflammation and Hepatic Diseases group at Hospital Clínic de Barcelona-IDIBAPS, Spain.
“These results highlight the beneficial effects of albumin to protect organs and tissues against inflammatory injury and oxidative stress, and accentuate the importance of maintaining the albumin levels within the normal range in patients with decompensated cirrhosis which present recurrent hypoalbuminemia”, concluded Clària, Principal Investigator at EF CLIF and Hospital Clínic de Barcelona-IDIBAPS, Spain.
This study was promoted by the European Foundation for the Study of Chronic Failure (EF CLIF). This study received funding from the Government of Catalonia, 2017SGR1449 and Ministerio de Ciencia e Innovación (MICINN), PID2019-105240RB-I00.
Other authors on the study are Glòria Garrabou, Roger Flores-Costa, Mireia Casulleras, Cristina López-Vicario, Ingrid W. Zhang, Judith Cantó-Santos, Bryan J. Contreras, María B. Sánchez-Rodríguez, Berta Romero-Grimaldo, Raquel Horrilo, Montserrat Costa, and Vicente Arroyo.
Duran-Güell, M.; Garrabou, G.; Flores-Costa, R.; Casulleras, M.; López-Vicario, C.; Zhang, I. W.; Cantó-Santos, J.; Contreras, B. J.; Sánchez-Rodríguez, M. B.; Romero-Grimaldo, B.; Horrillo, R.; Costa, M.; Arroyo, V.; Clària, J. Essential role for albumin in preserving liver cells from TNFα-induced mitochondrial injury. FASEB J 2023, 37 (3), e22817. . DOI: 10.1096/fj.202201526R
European Foundation for the Study of
Chronic Liver Failure
Travessera de Gràcia 11, 7th floor
08021 Barcelona, Spain
© European Foundation for the Study of Chronic Liver Failure 2024
